Tissue regenerative potential greatly varies across species and organs. Nevertheless, most organisms, including mammals, possess partial regenerative abilities in their juvenile stages, which is lost as the animal develops and tissue matures. This decline is correlated with the onset of thyroid gland organogenesis and the presence of systemic thyroid hormone in several species. For example, the frogs lose their limb regeneration ability during metamorphosis which is induced by thyroid hormones. On the contrary, axolotls (Ambystoma mexicanum) maintain a low level of the thyroid hormones and show remarkable tissue regeneration ability throughout their life whereas mouse with much higher thyroid level has the lowest tissue regeneration ability among all three. A previous study in axolotl suggests that L-thyroxine induced metamorphosis reduces regenerative rate and fidelity [1], supporting the idea that there is not only a correlative but also a causal relation between the thyroid signaling, metamorphosis and the regenerative ability. Although these facts have long been known, we do not understand the cellular and molecular mechanism by which the thyroid pathway exerts its anti-regenerative effects. In this proposal, we want to address the following fundamental questions. First, poor regenerative response caused by the thyroid hormone ? is it due to a systemic effect of the thyroid hormone or its direct effect on a specific cell type or is it both? Second, are metamorphosis and anti-regenerative properties of the thyroid hormone synergistic or can they be decoupled? Third, what does metamorphosis mean at a molecular level in the key cell type? Among all different possibilities, our central hypotheses are metamorphosis and poor regenerative behavior upon the thyroid treatment are coupled with each other and that the thyroid hormone treatment exerts its anti-regenerative and metamorphic effect by pushing fibroblasts to a further differentiated state. We provide compelling evidences based on literature and our preliminary data to support these hypotheses and we outline a series of experiments that will allow us to test our hypotheses and answer the aforementioned questions.